The Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily that is upregulated in diabetic tissues includeing the vasculature and glomerular epithelial cells. Previous studies have identified that the ligands of RAGE, such as AGEs and S1007calgranulins, are expressed to increased degrees in diabetic tissues. Previous studies have demonstrated that pharmacologic blockade of RAGE, using soluble RAGE, RAGE null mice or signal transduction deficient mutants, protects against several complications of diabetes, including in the vasculature the kidney. The purpose of this application is to explore in depth for the first time the implications of RAGE deletion in db/db mice. Db/db mice are a murine model of type 2, insulin-resistant diabetes. We hypothesize that the adverse impact of RAGE/ligand signaling will be attenuated in db/db mice that lack RAGE. We will perform a thorough time course to assess the impact of RAGE on the pathogenesis of diabetic nephropathy and diabetic vascular perturbations. In this application, we will dissect the impact of the RAGE/ligand interactions and the resulting signaling pathways using RAGE-expressing db/db mice and db/db mice genetically devoid of RAGE. [unreadable] [unreadable] [unreadable]